EP0034364B1 - New 20-substituted 3-oxo-pregn-4-ene steroid compounds and process for their preparation - Google Patents

New 20-substituted 3-oxo-pregn-4-ene steroid compounds and process for their preparation Download PDF

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EP0034364B1
EP0034364B1 EP81101114A EP81101114A EP0034364B1 EP 0034364 B1 EP0034364 B1 EP 0034364B1 EP 81101114 A EP81101114 A EP 81101114A EP 81101114 A EP81101114 A EP 81101114A EP 0034364 B1 EP0034364 B1 EP 0034364B1
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oxo
steroid
steroid compounds
compounds
substituted
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German (de)
French (fr)
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EP0034364A2 (en
EP0034364A3 (en
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Leroy O. Krbechek
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Henkel Corp
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Henkel Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C07J41/0061—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives one of the carbon atoms being part of an amide group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/005—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of only two carbon atoms, e.g. pregnane derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C07J9/005—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane containing a carboxylic function directly attached or attached by a chain containing only carbon atoms to the cyclopenta[a]hydrophenanthrene skeleton

Definitions

  • the invention relates to new 20-substituted steroid compounds which are important derivatives with a basic steroid structure and in particular important intermediates in the synthesis of progesterone and progesterone-like compounds from steroid compounds, for example of plant or animal origin, by degradation of the side chain substituent in C-17 of the steroid structure.
  • the invention further relates to the process for the preparation of these new 20-substituted steroid derivatives.
  • the subject of European patent application 004913 is a process for the preparation of 3-oxo-pregna-4-en-20-carboxylic acid ( ⁇ 4 -BNC) and / or 3-oxo-pregna-1,4-diene-20-carboxylic acid ( ⁇ 1,4 -BNC) by microbial side chain degradation on 17 C side chain steroid substrates.
  • Particularly suitable starting materials are sterols of animal and / or vegetable origin, such as cholesterol, sitosterol, stigmasterol and related compounds.
  • ⁇ 4 - and ⁇ 1,4 -BNC have become inexpensive, technically accessible starting materials for the production of progesterone and related compounds.
  • the BNC compounds mentioned here have in common the carboxyl group -COOH present as a 20-position substituent, which must be broken down on the way to progesterone, the 20-position still having to be converted to the oxo group.
  • the invention is based on the task of making a significant contribution to solving this problem.
  • new 20-substituted steroid compounds and the process for their preparation are described, by means of which a technically convenient route to progesterone or progesterone-like compounds is opened.
  • the invention relates in a first embodiment to new 20-substituted 3-0xo-pregna-4-ene and optionally at least one further double bond in the 1 (2) and / or 17 (20) position having steroid compounds of the general formula I.
  • X represents the group-CONH2, -NCO or -NHCOOR, in which R is a lower hydrocarbon radical, with the exception of 3-oxopregna-4-en-20-carboxamide.
  • A is the A'- 4 BNC
  • B is the A 4 BNC
  • C is the ⁇ 1,4,17 -BNC
  • D is the ⁇ 4,17 -BNC.
  • the corresponding 20-carboxamides are first described, ie the compounds in which X denotes the radical -CONH 2 .
  • New compounds in the context of the invention are furthermore the corresponding 20-isocyanates, ie the compounds according to A to D in which X is the radical -NCO.
  • the 20-carbamates in which in the formula pictures A to D the radical X has the meaning -NHCOOR, in which R is a lower hydrocarbon radical.
  • Suitable lower hydrocarbon radicals are in particular those having up to 10, preferably up to 5 and in particular up to 4, carbon atoms.
  • the methyl radical and the tert-butyl radical can be of particular importance.
  • Particularly preferred steroid derivatives in the sense of the invention can be the ⁇ 1.4 compounds according to A and the ⁇ 1.4.17 (20) compounds according to C and, if appropriate, also the ⁇ 4.17 (20) compounds according to D. .
  • All of the steroid compounds of the invention shown here are easily accessible by the method mentioned at the outset and can ultimately be converted to the 3,20-dioxo-steroid compounds of the progesterone type, as will be explained in more detail below.
  • the steroid-20-carbonyl halide is reacted with ammonia or an ammonia-providing compound to give the corresponding steroid-20-carbonamide.
  • the reaction with ammonia or ammonia-providing compounds is expediently carried out in the temperature range from ⁇ 20 ° C. to approximately 80 ° C. and preferably in the range from ⁇ 5 ° C. to approximately 35 ° C.
  • ammonium hydroxide is particularly suitable as the reactant which supplies ammonia. At least an equivalent amount of ammonia is required to form the acid amide from the halide, but another equivalent of basic component is required to bind the hydrogen halide liberated in the process. Accordingly, ammonia or the ammonia-providing compound is used in amounts of up to, for example, 5 equivalents, preferably in amounts of up to about 3 equivalents, amounts of about 1.2 to 3 equivalents and in particular of about 2 to 3 equivalents of ammonia per equivalent of acid halide can be particularly useful.
  • the reaction of the acid halide with ammonia or the compound providing ammonia is preferably carried out in an organic solvent.
  • halogenated organic solvents such as halogenated hydrocarbons and in particular methylene chloride are also particularly suitable here.
  • the reaction mixture When working with ammonium hydroxide as the ammonia-providing compound, the reaction mixture contains substantial amounts of water. A simple phase separation allows the desired connection to be obtained.
  • the organic phase is washed several times with water, preferably then dried with, for example, calcium sulfate and filtered.
  • the organic solvent is then removed in a known manner.
  • the carboxamido compound obtained can, if desired, be further purified by washing with an organic component, such as acetone, in order to obtain practically pure acid amide.
  • the reaction for isocyanate formation is usually carried out at temperatures from about 0 to 100 ° C., preferably in the range from about 5-50 ° C.
  • Lead tetraacetate is required in an equivalent amount to the steroid compound used and should preferably be used in a limited excess. Nevertheless, it is true that lead tetraacetate can generally be used in amounts of about 1.1 to 5 equivalents, based on the steroid compound, whereby working with 1.2 to 3 equivalents of lead tetraacetate can be preferred.
  • reaction of the carboxamide compound with lead tetraacetate is preferably carried out in an inert atmosphere and in the complete absence of water.
  • the reaction vessel is expediently flushed several times with sharply dried nitrogen in order to also remove traces of water from the reaction vessel.
  • the reaction is then carried out under dry nitrogen.
  • the isocyanate-containing organic solution can be washed with sodium thiosulfate and then with saturated saline to remove residual amounts of the lead salt from the reaction mixture.
  • the desired process product can finally be obtained by removing the solvent or by solvent extraction.
  • the isocyanate is reacted with a monohydric alcohol to give the carbamate.
  • Lower alcohols in particular lower alkanols, are particularly suitable as monohydric alcohols.
  • Alkanols having up to 10, preferably having up to 5, carbon atoms are suitable, for example, alkanols having 1 to 4 carbon atoms being particularly important.
  • Methanol and tert-butanol lead to steroid 20 carbamates which are particularly suitable in the context of the invention.
  • the isocyanates are also isolated in a previously isolated form or, if desired, without prior isolation brought together an at least equivalent amount of the alcohol. The alcohol is expediently used in excess.
  • the reaction takes place in a manner known per se and can accordingly be carried out, for example, at room temperature or only moderately elevated temperatures. Temperatures of 0-60 ° C can be suitable.
  • the alcohol used is expediently predried and in particular at least largely anhydrous in order to rule out undesirable side reactions.
  • the steroid 20 carbamates are stable compounds which can be isolated, for example, by removing the excess of alcohol and, if desired, can be further purified in a conventional manner.
  • the steroid 20 carbamates can then be hydrolytically cleaved to the steroid 20 amines, which can ultimately be converted into the compounds of the progesterone type. Details of these subsequent process steps which are not claimed in the context of the present invention can be found, for example, in the parallel European patent applications EP-A-81 101 115.4 (34365) ("Process for the preparation of 3,20-dioxo-pregn-4-enes and / or 3,20-Dioxopregna-1,4-diene ”, US priority of February 19, 1980, file number: 122,396) EP-A-81 101 118.8 (34367) (“ Process for the hydrolytic cleavage of steroid 20- Carbamates ”, US priority of February 19, 1980, file number: 122.321), EP-A-81 101 113.9 (34363) (“ New steroid compound with a 20-amino function and process for its preparation ”, US priorities of February 19, 1980 , File numbers 122397 and 122321).
  • 3-oxo-pregna-1,4-diene-20-carboxylic acid, 3-oxo-pregna-4-en-20-carboxylic acid, 3-oxo-pregna-1,4,17 (20) -triene-20-carboxylic acid and / or 3-oxo-pregna-4.17 (20) -diene-20-carboxylic acid are converted to the corresponding acid chlorides by reaction with thionyl chloride at 0 ° C. using a slight stoichiometric excess in methylene chloride. The reaction is essentially complete after 20 minutes. The acid chloride is isolated, purified and identified.
  • the acid chlorides obtained according to a) are reacted with concentrated aqueous ammonia solution at 0 ° C.
  • the amount of ammonia is at least twice the stoichiometrically required amount, but is expediently used in a surplus beyond that.
  • the acid chlorides are reacted as a solvent in methylene chloride.
  • the two liquid phases are separated from one another.
  • the aqueous phase is washed out several times with methylene chloride and the organic phase is separated off in each case.
  • the organic phases are combined, washed and the solution is evaporated to dryness.
  • the crude acid amide is purified by digestion with acetone and carefully dried on the oil pump for analysis.
  • the acid amides obtained in b) are dissolved in tetrahydrofuran and reacted under nitrogen with a slight excess of lead tetraacetate.
  • the entire reaction system had previously been purged by nitrogen purging.
  • the reaction mixture is stirred for a period of 1.5 hours, after which the reaction is complete.
  • Sodium thiosulfate is then added to reduce any excess lead salt that may still be present.
  • the reaction solution is washed a second time with aqueous thiosulfate and then three times with saturated saline. After phase separation and drying of the organic phase, the solvent is drawn off.
  • the isocyanate compounds are obtained as a residue.
  • the isocyanate compounds isolated according to c) are dissolved in an excess of a lower alcohol, for example a C-1 to C-4 alcohol, and in particular in methanol or tert-butanol and reacted. The excess alcohol is deducted. The carbamate formed is isolated.
  • a lower alcohol for example a C-1 to C-4 alcohol
  • methanol or tert-butanol for example in a C-1 to C-4 alcohol

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Steroid Compounds (AREA)

Abstract

The present invention discusses the production of useful steroids through starting with a steroid which has an acid side chain attached to the steroid ring structure. The present invention also describes and claims several novel compounds obtained through the described process.

Description

Die Erfindung betrifft neue 20-substituierte Steroidverbindungen, die bedeutungsvolle Derivate mit Steroidgrundstruktur und insbesondere wichtige Zwischenprodukte bei der Synthese von Progesteron und progesteronartigen Verbindungen aus Steroidverbindungen, beispielsweise pflanzlichen oder tierischen Ursprungs, durch Abbau des Seitenketten-Substituenten in C-17 des Steroidgerüsts sind. Weiterhin betrifft die Erfindung das Verfahren zur Herstellung dieser neuen 20-substituierten Steroidderivate.The invention relates to new 20-substituted steroid compounds which are important derivatives with a basic steroid structure and in particular important intermediates in the synthesis of progesterone and progesterone-like compounds from steroid compounds, for example of plant or animal origin, by degradation of the side chain substituent in C-17 of the steroid structure. The invention further relates to the process for the preparation of these new 20-substituted steroid derivatives.

Gegenstand der offengelegten Europäischen Patentanmeldung 004913 ist u. a. ein Verfahren zur Herstellung von 3-Oxo-pregna-4-en-20-carbonsäure (Δ4-BNC) und/oder 3-Oxo-pregna-1,4-dien-20-carbonsäure (Δ1,4-BNC) durch mikrobiellen Seitenkettenabbau an 17-C-Seitenketten-Steroidsubstraten. Besonders geeignete Ausgangsmaterialien sind Sterine tierischen und/oder pflanzlichen Ursprungs, wie Cholesterin, Sitosterin, Stigmasterin und verwandte Verbindungen. Δ4- und Δ1,4-BNC sind hierdurch wohlfeile, technisch zugängliche Ausgangsmaterialien für die Gewinnung von Progesteron und verwandten Verbindungen geworden. Die Europäische Patentanmeldung EP-A-81 100146.0 (33439) beschreibt eine Modifikation des Verfahrens, durch die 3-Oxo-pregna-1,4,17(20)-carbonsäure (Δ1,4,17(20)-BNC) in entsprechender Weise zugänglich geworden ist. Die Herstellung von 3-Oxopregna-4,17(20)-dien-20-carbonsäure (Δ4,17(20)-BNC) durch mikrobiellen Seitenkettenabbau an Steroidsubstraten wird in der US-PS 3 994 933 geschildert.The subject of European patent application 004913 is a process for the preparation of 3-oxo-pregna-4-en-20-carboxylic acid (Δ 4 -BNC) and / or 3-oxo-pregna-1,4-diene-20-carboxylic acid (Δ 1,4 -BNC) by microbial side chain degradation on 17 C side chain steroid substrates. Particularly suitable starting materials are sterols of animal and / or vegetable origin, such as cholesterol, sitosterol, stigmasterol and related compounds. As a result, Δ 4 - and Δ 1,4 -BNC have become inexpensive, technically accessible starting materials for the production of progesterone and related compounds. The European patent application EP-A-81 100146.0 (33439) describes a modification of the method by which 3-oxo-pregna-1,4,17 (20) -carboxylic acid (Δ 1,4,17 (20) -BNC) in has become accessible accordingly. The preparation of 3-oxopregna-4.17 (20) -diene-20-carboxylic acid (Δ 4.17 (20) -BNC) by microbial side chain degradation on steroid substrates is described in US Pat. No. 3,994,933.

Den hier genannten BNC-Verbindungen ist die als Substituent in 20-Stellung vorliegende Carboxylgruppe -COOH gemeinsam, die auf dem Wege zum Progesteron abgebaut werden muß, wobei weiterhin die 20-Stellung zur Oxogruppe umzuwandeln ist.The BNC compounds mentioned here have in common the carboxyl group -COOH present as a 20-position substituent, which must be broken down on the way to progesterone, the 20-position still having to be converted to the oxo group.

Die Erfindung geht von der Aufgabe aus, einen wesentlichen Beitrag zur Lösung dieser Problemstellung zu liefern. In der technischen Lösung dieser erfindungsgemäßen Aufgabe werden neue 20- substituierte Steroidverbindungen und das Verfahren zu ihrer Herstellung beschrieben, mittels deren ein technisch bequem gangbarer Weg zum Progesteron bzw. zu progesteronartigen Verbindungen geöffnet wird.The invention is based on the task of making a significant contribution to solving this problem. In the technical solution to this problem according to the invention, new 20-substituted steroid compounds and the process for their preparation are described, by means of which a technically convenient route to progesterone or progesterone-like compounds is opened.

Gegenstand der Erfindung sind dementsprechend in einer ersten Ausführungsform neue 20-substituierte 3-0xo-pregna-4-en- sowie ggf. wenigstens eine weitere Doppelbindung in 1 (2)- und/oder 17 (20)-Stellung aufweisende Steroidverbindungen der allgemeinen Formel I

Figure imgb0001
in der X die Gruppe-CONH2, -NCO oder -NHCOOR bedeutet, worin R ein niederer Kohlenwasserstoffrest ist, mit Ausnahme von 3-Oxopregna-4-en-20-carboxamid.Accordingly, the invention relates in a first embodiment to new 20-substituted 3-0xo-pregna-4-ene and optionally at least one further double bond in the 1 (2) and / or 17 (20) position having steroid compounds of the general formula I.
Figure imgb0001
 in which X represents the group-CONH2, -NCO or -NHCOOR, in which R is a lower hydrocarbon radical, with the exception of 3-oxopregna-4-en-20-carboxamide.

Gegenstand der Erfindung ist in einer weiteren Ausführungsform das Verfahren zur Herstellung von 20-substituierten 3-0xo-pregna-4-en- sowie ggf. wenigstens eine weitere Doppelbindung in 1 (2)-und/oder 17(20)-Stellung aufweisenden Steroidverbindungen der zuvor angegebenen allgemeinen Formel I, wobei dieses Verfahren dadurch gekennzeichnet ist, daß man von den der allgemeinen Formel 1 entsprechenden 20-Carbonsäuren (X = -COOH) ausgehend zunächst das 20-Carbonsäurehalogenid (X = ―CO―Halogen) herstellt und dieses mit Ammoniak oder Ammoniak liefernden Verbindungen zum 20-Carbonsäureamid (X = ―CONH2) umsetzt, gewünschtenfalls dieses durch Umsetzung mit Bleitetraacetat in das 20-Isocyanat (X = -NCO) umwandelt und gewünschtenfalls durch Anlagerung eines Alkohols ROH (worin R die angegebene Bedeutung hat) das 20-Carbamat (X = -NHCOOR) gewinnt.In a further embodiment, the invention relates to the process for the preparation of 20-substituted 3-0xo-pregna-4-enes and, if appropriate, at least one further double bond in steroid compounds having a 1 (2) and / or 17 (20) position of the general formula I given above, this process being characterized in that starting from the 20-carboxylic acids corresponding to the general formula 1 (X = -COOH), the 20-carboxylic acid halide (X = ―CO ― halogen) is first prepared and this with Converting ammonia or ammonia-providing compounds to the 20-carboxamide (X = ―CONH 2 ), if desired converting this to the 20-isocyanate (X = -NCO) by reaction with lead tetraacetate and if desired by addition of an alcohol ROH (in which R has the meaning given ) the 20-carbamate (X = -NHCOOR) wins.

Die vier durch die Erfindung betroffenen Grundtypen an Steroidverbindungen sind in den folgenden Formelbildern A bis D aufgezeigt.

Figure imgb0002
Figure imgb0003
Figure imgb0004
 The four basic types of steroid compounds affected by the invention are shown in the following formulas A to D.
Figure imgb0002
Figure imgb0003
Figure imgb0004

Bedeutet X die Carboxylgruppe -COOH, dann stellt A die A'-4-BNC dar, B ist die A4-BNC, C ist die Δ1,4,17-BNC und D ist die Δ4,17-BNC.If X is the carboxyl group -COOH, then A is the A'- 4 BNC, B is the A 4 BNC, C is the Δ 1,4,17 -BNC and D is the Δ 4,17 -BNC.

Als neue Verbindungen der Erfindung zu diesen vier Grundstrukturen werden zunächst die entsprechenden 20-Carbonsäureamide geschildert, d. h. die Verbindungen, in denen X den Rest -CONH2 bedeutet. Neue Verbindungen im Sinne der Erfindung sind weiterhin die entsprechenden 20-Isocyanate, d. h. die Verbindungen gemäß A bis D, bei denen X der Rest -NCO ist. Ebenfalls neue Verbindungen im Sinne der Erfindung sind schließlich die 20-Carbamate, bei denen in den Formelbildern A bis D der Rest X die Bedeutung -NHCOOR hat, worin R eine niederer Kohlenwasserstoffrest ist. Als niederer Kohlenwasserstoffrest kommen insbesondere solche mit bis zu 10, vorzugsweise mit bis zu 5 und insbesondere mit bis zu 4 C-Atomen in Betracht. Dem Methylrest und dem tert.-Butylrest können besondere Bedeutung zukommen.As new compounds of the invention to these four basic structures, the corresponding 20-carboxamides are first described, ie the compounds in which X denotes the radical -CONH 2 . New compounds in the context of the invention are furthermore the corresponding 20-isocyanates, ie the compounds according to A to D in which X is the radical -NCO. Finally, likewise new compounds in the sense of the invention are the 20-carbamates, in which in the formula pictures A to D the radical X has the meaning -NHCOOR, in which R is a lower hydrocarbon radical. Suitable lower hydrocarbon radicals are in particular those having up to 10, preferably up to 5 and in particular up to 4, carbon atoms. The methyl radical and the tert-butyl radical can be of particular importance.

Besonders bevorzugte Steroidderivate im Sinne der Erfindung können die Δ1,4-Verbindungen gemäß A und die Δ1,4,17(20)-Verbindungen gemäß C sowie ggf. auch noch die Δ4,17(20)-Verbindungen gemäß D sein.Particularly preferred steroid derivatives in the sense of the invention can be the Δ 1.4 compounds according to A and the Δ 1.4.17 (20) compounds according to C and, if appropriate, also the Δ 4.17 (20) compounds according to D. .

Alle hier dargestellten Steroidverbindungen der Erfindung sind durch das eingangs erwähnte Verfahren bequem zugänglich und lassen sich letzlich zu den 3,20-Dioxo-Steroidverbindungen vom Progesteron-Typ umwandeln, wie noch im einzelnen dargestellt wird.All of the steroid compounds of the invention shown here are easily accessible by the method mentioned at the outset and can ultimately be converted to the 3,20-dioxo-steroid compounds of the progesterone type, as will be explained in more detail below.

Das erfindungsgemäße Herstellungsverfahren geht von den Steroid-20-Carbonsäuren gemäß Formelbildern A bis D aus, und überführt diese in einer ersten Stufe in die Carbonsäurehalogenide, die dann ihrerseits zu den 20-Carboxamiden umgewandelt werden. Die Umwandlung solcher Carbonsäuren in die Carbonsäurehalogenide, insbesondere in die entsprechenden Chloride, wird in der älteren Europäischen Patentanmeldung EP-A-81 100 145.2 (34248) beschrieben und beansprucht. Im einzelnen gilt das Folgende :

  • Eine oder mehrere der genannten Säuren werden in Form der freien Säure als Salz oder als hydrolysierbarer Ester mit einem anorganischen Halogenierungsmittel behandelt. Besonders geeignete Halogenierungsmittel sind Thionylchlorid und Thionylbromid, aber auch andere bekannte Halogenierungsmittel, wie Phosphortrichlorid, Phosphorpentachlorid, Phosphoroxychlorid, und die entsprechenden Bromide können ggf. Verwendung finden. Bevorzugt wird ein Chlorierungsmittel und insbesondere Thionylchlorid eingesetzt. Bevorzugt wird die Chlorierung bei niederen Temperaturen, insbesondere im Bereich von etwa - 20 °C bis + 20 °C, vorzugsweise bei Temperaturen nicht über 15 °C, durchgeführt. Das Chlorierungsmittel wird in wenigstens äquivalenter Menge zur vorgelegten Säure eingesetzt. Zur Vermeidung von unerwünschten Nebenreaktionen, die insbesondere bei Steroidverbindungen mit mehr als nur einer Doppelbindung im System auftreten können, kann es zweckmäßig sein, mit einem nur sehr begrenzten Überschuß des Halogenierungsmittels zu arbeiten, der beispielsweise nicht mehr als 20 %, vorzugsweise nicht mehr als 10 %, der stöchiometrisch benötigten Menge ausmacht. Geeignete Reaktionsbedingungen vorausgesetzt, kann allerdings auch mit größeren Mengen, z. B. im Bereich von 1,1 bis 5,0 Aquivalenten, insbesondere bis zu 3,0 Äquivalenten, des Halogenierungsmittels gearbeitet werden. Die Halogenierung kann in Gegenwart von Lösungsmitteln durchgeführt werden. Geeignete Lösungsmittel sind beispielsweise Halogenkohlenwasserstoffe, wie Methylenchlorid oder Ethylendichlorid. Zweckmäßigerweise wird das Halogenierungsmittel der vorgelegten Lösung der Steroidverbindung im Lösungsmittel langsam zugesetzt. Das Halogenierungsmittel sollte so rein wie möglich sein. Es kann zweckmäßig sein, das Halogenierungsmittel vor der Verwendung einem speziellen Reinigungsschritt durch Behandlung mit ungesättigten Verbindungen, wie Leinöl oder insbesondere Squalen, zu unterwerfen. Diese ungesättigten Komponenten reagieren offenbar mit den Verunreinigungen im Halogenierungsmittel. Hierdurch wird die Bildung von unerwünschten Nebenprodukten verringert. Auch die Mitverwendung eines tertiären Amins, wie Pyridin, hat sich als hilfsreich zur Erzielung hoher Ausbeuten an reinem Säurehalogenid erwiesen.
The production process according to the invention starts from the steroid-20-carboxylic acids according to formula pictures A to D, and converts them in a first stage into the carboxylic acid halides, which in turn are then converted to the 20-carboxamides. The conversion of such carboxylic acids into the carboxylic acid halides, in particular into the corresponding chlorides, is described and claimed in the earlier European patent application EP-A-81 100 145.2 (34248). The following applies in particular:
  • One or more of the acids mentioned are treated in the form of the free acid as a salt or as a hydrolyzable ester with an inorganic halogenating agent. Particularly suitable halogenating agents are thionyl chloride and thionyl bromide, but also other known halogenating agents, such as phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, and the corresponding bromides can optionally be used. A chlorinating agent and in particular thionyl chloride are preferably used. The chlorination is preferably carried out at low temperatures, in particular in the range from about -20 ° C. to + 20 ° C., preferably at temperatures not above 15 ° C. The chlorinating agent is used in at least an equivalent amount to the acid introduced. To avoid undesirable side reactions, which can occur in particular in the case of steroid compounds with more than just one double bond in the system, it may be expedient to work with a very limited excess of the halogenating agent, for example not more than 20%, preferably not more than 10 %, which makes up the stoichiometrically required amount. Appropriate reaction conditions provided, but can also with larger amounts, eg. B. in the range of 1.1 to 5.0 equivalents, in particular up to 3.0 equivalents, of the halogenating agent. The halogenation can be carried out in the presence of solvents. Suitable solvents are, for example, halogenated hydrocarbons, such as Methylene chloride or ethylene dichloride. The halogenating agent is expediently slowly added to the solution of the steroid compound in the solvent. The halogenating agent should be as pure as possible. It may be appropriate to subject the halogenating agent to a special cleaning step by treatment with unsaturated compounds, such as linseed oil or in particular squalene, before use. These unsaturated components apparently react with the contaminants in the halogenating agent. This reduces the formation of unwanted by-products. The use of a tertiary amine, such as pyridine, has also proven to be helpful in achieving high yields of pure acid halide.

In der nächsten Stufe des erfindungsgemäßen Verfahrens wird das Steroid-20-Carbonylhalogenid mit Ammoniak oder einer Ammoniak liefernden Verbindung zum entsprechenden Steroid-20-Carbonamid umgesetzt. Die Umsetzung mit Ammoniak bzw. Ammoniak liefernden Verbindungen wird zweckmäßigerweise im Temperaturbereich von - 20 °C bis etwa 80 °C und vorzugsweise im Bereich von - 5 °C bis etwa 35 °C durchgeführt.In the next step of the process according to the invention, the steroid-20-carbonyl halide is reacted with ammonia or an ammonia-providing compound to give the corresponding steroid-20-carbonamide. The reaction with ammonia or ammonia-providing compounds is expediently carried out in the temperature range from −20 ° C. to approximately 80 ° C. and preferably in the range from −5 ° C. to approximately 35 ° C.

Neben Ammoniak ist insbesondere Ammoniumhydroxid als Ammoniak liefernder Reaktant geeignet. Zur Bildung des Säureamids aus dem Halogenid wird wenigstens ein äquivalenter Betrag an Ammoniak benötigt, allerdings wird zur Bindung des dabei freiwerdenden Halogenwasserstoffs ein weiteres Äquivalent an basischer Komponente erforderlich. Ammoniak bzw. die Ammoniak liefernde Verbindung wird dementsprechend im Mengen bis zu beispielsweise 5 Äquivalenten, vorzugsweise in Mengen bis zu etwa 3 Äquivalenten, eingesetzt, wobei Mengen von etwa 1,2 bis 3 Äquivalenten und insbesondere von etwa 2 bis 3 Äquivalenten Ammoniak je Äquivalent Säurehalogenid besonders zweckmäßig sein können.In addition to ammonia, ammonium hydroxide is particularly suitable as the reactant which supplies ammonia. At least an equivalent amount of ammonia is required to form the acid amide from the halide, but another equivalent of basic component is required to bind the hydrogen halide liberated in the process. Accordingly, ammonia or the ammonia-providing compound is used in amounts of up to, for example, 5 equivalents, preferably in amounts of up to about 3 equivalents, amounts of about 1.2 to 3 equivalents and in particular of about 2 to 3 equivalents of ammonia per equivalent of acid halide can be particularly useful.

Die Umsetzung des Säurehalogenids mit Ammoniak bzw. der Ammoniak liefernden Verbindung wird vorzugsweise in einem organischen Lösungsmittel durchgeführt. Auch hier sind halogenierte organische Lösungsmittel, wie Halogen-Kohlenwasserstoffe und insbesondere Methylenchlorid, besonders geeignet.The reaction of the acid halide with ammonia or the compound providing ammonia is preferably carried out in an organic solvent. Halogenated organic solvents such as halogenated hydrocarbons and in particular methylene chloride are also particularly suitable here.

Wird mit Ammoniumhydroxid als Ammoniak liefernder Verbindung gearbeitet, so enthält das Reaktionsgemisch substantielle Wassermengen. Eine einfache Phasentrennung erlaubt die Gewinnung der gewünschten Verbindung. Die organische Phase wird mehrfach mit Wasser gewaschen, vorzugsweise anschließend mit beispielsweise Calciumsulfat getrocknet und gefiltert. Das organische Lösungsmittel wird dann in bekannter Weise entfernt. Die angefallene Carboxamidoverbindung kann gewünschtenfalls durch Auswaschen mit einer organischen Komponente, wie Aceton, weitergereinigt werden, um praktisch reines Säureamid zu erhalten.When working with ammonium hydroxide as the ammonia-providing compound, the reaction mixture contains substantial amounts of water. A simple phase separation allows the desired connection to be obtained. The organic phase is washed several times with water, preferably then dried with, for example, calcium sulfate and filtered. The organic solvent is then removed in a known manner. The carboxamido compound obtained can, if desired, be further purified by washing with an organic component, such as acetone, in order to obtain practically pure acid amide.

Das erfindungsgemäße Verfahren sieht in einer weiterführenden Stufe vor, gewünschtenfalls die so gewonnenen Säureamide zu den Steroid-20-lsocyanatverbindungen und ggf. zu den 20-Carbamatverbindungen umzuwandeln. Es ist dabei möglich, die Isocyanate als solche zu isolieren und sie gewünschtenfalls in einer getrennten Verfahrensstufe in die Carbamate umzuwandeln, möglich ist aber auch die Verbindung dieser beiden Verfahrensstufen zu einem in einem Zuge durchgeführten Verfahrensschritt. Im letzteren Fall wird das intermediär gebildete 20-Isocyanat in situ zum entsprechenden Carbamat umgewandelt. Im einzelnen gilt hier das Folgende :

  • Wird die isolierte Herstellung der Steroid-20-lsocyanate gewünscht, dann werden die Steroid-20-Carboxamide mit einer wenigstens äquivalenten Menge an Bleitetraacetat in Gegenwart eines nichtwäßrigen aprotischen Lösungsmittels umgesetzt, anschließend wird die organische Phase abgetrennt, das Lösungsmittel entfernt und die 20-Isocyanatverbindung isoliert. Die Lösungsmittel müssen hier aprotischer Natur sein, andernfalls würde das Isocyanat in unerwünschter Weise mit dem Lösungsmittel weiter reagieren. Ein geeignetes Lösungsmittel für diese Verfahrensmodifikation is beispielsweise Tetrahydrofuran.
In a further step, the process according to the invention provides for, if desired, converting the acid amides thus obtained to the steroid 20-isocyanate compounds and, if appropriate, to the 20-carbamate compounds. It is possible to isolate the isocyanates as such and, if desired, convert them to the carbamates in a separate process step, but it is also possible to combine these two process steps in one process step. In the latter case, the intermediate 20-isocyanate is converted in situ to the corresponding carbamate. The following applies here in detail:
  • If the isolated preparation of the steroid 20 isocyanates is desired, then the steroid 20 carboxamides are reacted with an at least equivalent amount of lead tetraacetate in the presence of a non-aqueous aprotic solvent, then the organic phase is separated off, the solvent is removed and the 20 isocyanate compound isolated. The solvents here must be of an aprotic nature, otherwise the isocyanate would react undesirably with the solvent. A suitable solvent for this process modification is, for example, tetrahydrofuran.

Die Umsetzung zur Isocyanatbildung wird üblicherweise bei Temperaturen von etwa 0 bis 100 °C, vorzugsweise im Bereich von etwa 5-50 °C, durchgeführt. Bleitetraacetat ist in äquivalenter Menge zur eingesetzten Steroidverbindung erforderlich und sollte bevorzugt in nur beschränktem Überschuß eingesetzt werden. Gleichwohl gilt, daß Bleitetraacetat grundsätzlich in Mengen von etwa 1,1 bis 5 Äquivalenten, bezogen auf Steroidverbindung, Verwendung finden kann, wobei das Arbeiten mit 1,2 bis 3 Äquivalenten Bleitetraacetat bevorzugt sein kann.The reaction for isocyanate formation is usually carried out at temperatures from about 0 to 100 ° C., preferably in the range from about 5-50 ° C. Lead tetraacetate is required in an equivalent amount to the steroid compound used and should preferably be used in a limited excess. Nevertheless, it is true that lead tetraacetate can generally be used in amounts of about 1.1 to 5 equivalents, based on the steroid compound, whereby working with 1.2 to 3 equivalents of lead tetraacetate can be preferred.

Bevorzugt wird die Umsetzung der Carboxamidverbindung mit Bleitetraacetat in inerter Atmosphäre und in vollständiger Abwesenheit von Wasser durchgeführt. Hierzu wird das Reaktionsgefäß zweckmäßigerweise mehrfach mit scharf getrocknetem Stickstoff gespült, um auch Spuren von Wasser aus dem Reaktionsgefäß zu entfernen. Die Reaktion wird dann unter trockenem Stickstoff durchgeführt.The reaction of the carboxamide compound with lead tetraacetate is preferably carried out in an inert atmosphere and in the complete absence of water. For this purpose, the reaction vessel is expediently flushed several times with sharply dried nitrogen in order to also remove traces of water from the reaction vessel. The reaction is then carried out under dry nitrogen.

Die Isocyanat enthaltende organische Lösung kann mit Natriumthiosulfat und dann mit gesättigter Kochsalzlösung gewaschen werden, um restliche Mengen des Bleisalzes aus dem Reaktionsgemisch zu entfernen. Das gewünschte Verfahrensprodukt kann schließlich durch Entfernung des Lösungsmittels bzw. durch Lösungsmittelextraktion gewonnen werden.The isocyanate-containing organic solution can be washed with sodium thiosulfate and then with saturated saline to remove residual amounts of the lead salt from the reaction mixture. The desired process product can finally be obtained by removing the solvent or by solvent extraction.

In der erfindungsgemäß gewünschtenfalls durchgeführten nächsten Verfahrensstufe wird das Isocyanat mit einem einwertigen Alkohol zum Carbamat umgesetzt. Als einwertige Alkohole kommen insbesondere niedere Alkohole, insbesondere niedere Alkanole, in Betracht. Geeignet sind beispielsweise Alkanole mit bis zu 10, vorzugsweise mit bis zu 5 Kohlenstoffatomen, wobei Alkanolen mit 1 bis 4 Kohlenstoffatomen besondere Bedeutung zukommen kann. Methanol und tert.-Butanol führen zu im Rahmen der Erfindung besonders geeigneten Steroid-20-Carbamaten. Zur Gewinnung der Carbamate werden die Isocyanate in zuvor isolierter Form oder gewünschtenfalls auch ohne vorherige Isolierung mit einer wenigstens äquivalenten Menge des Alkohols zusammengebracht. Zweckmäßigerweise wird der Alkohol im Überschuß eingesetzt. Die Reaktion erfolgt in an sich bekannter Weise und kann dementsprechend beispielsweise bei Raumtemperatur oder nur mäßig erhöhten Temperaturen vorgenommen werden. Temperaturen von 0-60 °C können geeignet sein. Der eingesetzte Alkohol ist zweckmäßigerweise vorgetrocknet und insbesondere wenigstens weitgehend wasserfrei, um unerwünschte Nebenreaktionen auszuschließen.In the next process step, if desired, carried out according to the invention, the isocyanate is reacted with a monohydric alcohol to give the carbamate. Lower alcohols, in particular lower alkanols, are particularly suitable as monohydric alcohols. Alkanols having up to 10, preferably having up to 5, carbon atoms are suitable, for example, alkanols having 1 to 4 carbon atoms being particularly important. Methanol and tert-butanol lead to steroid 20 carbamates which are particularly suitable in the context of the invention. To obtain the carbamates, the isocyanates are also isolated in a previously isolated form or, if desired, without prior isolation brought together an at least equivalent amount of the alcohol. The alcohol is expediently used in excess. The reaction takes place in a manner known per se and can accordingly be carried out, for example, at room temperature or only moderately elevated temperatures. Temperatures of 0-60 ° C can be suitable. The alcohol used is expediently predried and in particular at least largely anhydrous in order to rule out undesirable side reactions.

Die Steroid-20-Carbamate sind stabile Verbindungen, die beispielsweise durch Abziehen des Alkoholüberschusses isoliert und in konventioneller Weise gewünschtenfalls weitergereinigt werden können.The steroid 20 carbamates are stable compounds which can be isolated, for example, by removing the excess of alcohol and, if desired, can be further purified in a conventional manner.

Die Steroid-20-Carbamate können anschließend hydrolytisch zu den Steroid-20-Aminen gespalten werden, die letztlich zu den Verbindungen vom Progesteron-Typ umgesetzt werden können. Einzelheiten zu diesen nachfolgenden, im Rahmen der vorliegenden Erfindung nicht mitbeanspruchten Verfahrensschritten finden sich beispielsweise in den parallelen Europäischen Patentanmeldungen EP-A-81 101 115.4 (34365) (« Verfahren zur Herstellung von 3,20-Dioxo-pregn-4-en und/oder 3,20-Dioxo- pregna-1,4-dien », US-Priorität vom 19. Februar 1980, Aktenzeichen : 122,396) EP-A-81 101 118.8 (34367) (« Verfahren zur hydrolytischen Spaltung von Steroid-20-Carbamaten », U.S. Priorität vom 19. Februar 1980, Aktenzeichen : 122,321), EP-A-81 101 113.9 (34363) (« Neue Steroidverbindung mit einer 20-AminoFunktion und Verfahren zu ihrer Herstellung », US-Prioritäten vom 19. Februar 1980, Aktenzeichen 122397 und 122321).The steroid 20 carbamates can then be hydrolytically cleaved to the steroid 20 amines, which can ultimately be converted into the compounds of the progesterone type. Details of these subsequent process steps which are not claimed in the context of the present invention can be found, for example, in the parallel European patent applications EP-A-81 101 115.4 (34365) ("Process for the preparation of 3,20-dioxo-pregn-4-enes and / or 3,20-Dioxopregna-1,4-diene ”, US priority of February 19, 1980, file number: 122,396) EP-A-81 101 118.8 (34367) (“ Process for the hydrolytic cleavage of steroid 20- Carbamates ”, US priority of February 19, 1980, file number: 122.321), EP-A-81 101 113.9 (34363) (“ New steroid compound with a 20-amino function and process for its preparation ”, US priorities of February 19, 1980 , File numbers 122397 and 122321).

Es sind zahlreiche chemische Transformationen an Steroidverbindungen im Stand der Technik bekanntgeworden. Gleichwohl sind die hier beanspruchten Produkte mit Steroidstruktur und das Verfahren zu ihrer Herstellung bisher nicht bekannt geworden. Aus dem umfangreichen Stand der Technik seien die folgenden Literaturstellen benannt : JACS, Band 70, No. 3 (1948), S. 887 ; US-PS 4 088 760 ; US-PS 2 566 336 ; GB-PS 1 043 018 ; US-PS 2 731 461 ; Chemische Berichte, Jahrgang 88, No. 6 (1955), S. 883-894 ; US-PS 2 752 369 ; US-PS 3 519 658 ; J. Am. Chem. Soc. 1956, S. 524 ff. ; Tetrahedron Letters No. 18, (1964) S. 1053 bis 1061 ; J. Am. Chem. Soc., Band 91 (1969), S. 1429-1432 und Band 97 (1975), S. 6900-6901 ; Helvetica Chemica Acta, Band 32, Teil V (1949), No. 233, S. 1764 ; a.a.O. Band 32, Teil V (1949), No. 232, S. 1758 ; a.a.O. Band 32, Teil VI (1949), No. 255, S. 1922.Numerous chemical transformations on steroid compounds have become known in the art. Nevertheless, the products with the steroid structure claimed here and the process for their production have hitherto not become known. The following references from the extensive state of the art are mentioned: JACS, volume 70, no. 3 (1948), p. 887; U.S. Patent 4,088,760; U.S. Patent 2,566,336; GB-PS 1,043,018; U.S. Patent 2,731,461; Chemical reports, year 88, no. 6 (1955), pp. 883-894; U.S. Patent 2,752,369; U.S. Patent 3,519,658; J. Am. Chem. Soc. 1956, pp. 524 ff.; Tetrahedron Letters No. 18, (1964) pp. 1053-1061; J. Am. Chem. Soc., Vol. 91 (1969), pp. 1429-1432 and Vol. 97 (1975), pp. 6900-6901; Helvetica Chemica Acta, Volume 32, Part V (1949), No. 233, p. 1764; a.a.O. Volume 32, Part V (1949), No. 232, p. 1758; a.a.O. Volume 32, Part VI (1949), No. 255, p. 1922.

Beispielexample a) Herstellung der Säurechloridea) Preparation of the acid chlorides

3-Oxo-pregna-1,4-dien-20-carbonsäure, 3-Oxo-pregna-4-en-20-carbonsäure, 3-Oxo-pregna-1,4,17(20)-trien-20-carbonsäure und/oder 3-Oxo-pregna-4,17(20)-dien-20-carbonsäure werden durch Umsetzung mit Thionylchlorid bei 0 °C unter Verwendung eines leichten stöchiometrischen Überschusses in Methylenchlorid zu den entsprechenden Säurechloriden umgewandelt. Die Reaktion ist nach 20 Minuten im wesentlichen abgeschlossen. Das Säurechlorid wird isoliert, gereinigt und identifiziert.3-oxo-pregna-1,4-diene-20-carboxylic acid, 3-oxo-pregna-4-en-20-carboxylic acid, 3-oxo-pregna-1,4,17 (20) -triene-20-carboxylic acid and / or 3-oxo-pregna-4.17 (20) -diene-20-carboxylic acid are converted to the corresponding acid chlorides by reaction with thionyl chloride at 0 ° C. using a slight stoichiometric excess in methylene chloride. The reaction is essentially complete after 20 minutes. The acid chloride is isolated, purified and identified.

Im folgenden wird die entsprechende Darstellung des Δ1,4,117-BNC-Chlorids beschrieben, die Herstellung der anderen Säurechloride erfolgt in entsprechender Weise.The corresponding representation of the Δ 1,4,117 -BNC chloride is described below; the other acid chlorides are prepared in a corresponding manner.

17 g (50 mmol) Δ1,4,17-BNC in 100 ml absolutem Methylenchlorid werden bei 0°C mit 4,0 ml (55 mmol) frisch über Squalen-destilliertem Thionylchlorid versetzt und 20 Minuten bei 0 °C gerührt. Danach werden das Lösungsmittel und überschüssiges Thionylchlorid bei der gleichen Temperatur im Vakuum entfernt. Der Rückstand wird wieder in Methylenchlorid aufgenommen und die Lösung nochmals zur Trockne eingehängt. Der Rückstand ist für weitere Umsetzungen zu verwenden. Um ein zur Analyse geeignetes Säurechlorid zu erhalten, wird das rohe Säurechlorid mit absolutem Äther digeriert und nach dem Abziehen des Äthers sorgfältig an der Ölpumpe getrocknet.17 g (50 mmol) of Δ 1,4,17 -BNC in 100 ml of absolute methylene chloride are mixed with 4.0 ml (55 mmol) of freshly squalene-distilled thionyl chloride at 0 ° C. and stirred at 0 ° C. for 20 minutes. The solvent and excess thionyl chloride are then removed in vacuo at the same temperature. The residue is taken up again in methylene chloride and the solution is hung up again to dryness. The backlog is to be used for further implementations. In order to obtain an acid chloride suitable for analysis, the crude acid chloride is digested with absolute ether and, after removing the ether, carefully dried on an oil pump.

ElementaranalyseElemental analysis

Figure imgb0005
Figure imgb0005

b) Herstellung der Säureamideb) Preparation of the acid amides

Die gemäß a) gewonnenen Säurechloride werden mit konzentrierter wäßriger Ammoniaklösung bei 0°C zur Umsetzung gebracht. Die Ammoniakmenge beträgt dabei wenigstens das Doppelte des stöchiometrisch benötigten Betrages, wird jedoch zweckmäßigerweise in einem darüberhinausgehenden Überschluß eingesetzt. Die Säurechloride werden in Methylenchlorid als Lösungsmittel gelöst zur Umsetzung gebracht.The acid chlorides obtained according to a) are reacted with concentrated aqueous ammonia solution at 0 ° C. The amount of ammonia is at least twice the stoichiometrically required amount, but is expediently used in a surplus beyond that. The acid chlorides are reacted as a solvent in methylene chloride.

Nach Abschluß der Reaktion werden die beiden Flüssigphasen voneinander getrennt. Die wäßrige Phase wird mehrfach mit Methylenchlorid ausgewaschen und jeweils die organische Phase wieder abgetrennt. Die organischen Phasen werden vereinigt, gewaschen und die Lösung zur Trockne eingeengt. Das rohe Säureamid wird durch Digerieren mit Aceton gereinigt und zur Analyse sorgfältig an der Ölpumpe getrocknet.After the reaction has ended, the two liquid phases are separated from one another. The aqueous phase is washed out several times with methylene chloride and the organic phase is separated off in each case. The organic phases are combined, washed and the solution is evaporated to dryness. The crude acid amide is purified by digestion with acetone and carefully dried on the oil pump for analysis.

AnalysenwerteAnalytical values

  • Δ1,4-BNC-AmidΔ 1,4 -BNC amide
  • Fp : 235-238 °CMp: 235-238 ° C
Elementaranalyse :Elemental analysis:

Figure imgb0006
Figure imgb0006

1H-NMR-Spektrum (90 MHz, CDCl3, δ-Werte) :

Figure imgb0007

  • ― olefinische Protonen : ABC-System mit Signalen bei : 6,03 ; 6,11 ; 6,13 ; 6,22 ; 6,25 ; 7,00 ; 7,11 ppm
  • Δ4-BNC-Amid
  • Fp : 183-185 °C
1 H-NMR spectrum (90 MHz, CDCl 3 , δ values):
Figure imgb0007
  • - olefinic protons: ABC system with signals at: 6.03; 6.11; 6.13; 6.22; 6.25; 7.00; 7.11 ppm
  • Δ 4 -BNC amide
  • Mp: 183-185 ° C

ElementaranalyseElemental analysis

Figure imgb0008
Figure imgb0008

1H-NMR-Spektrum (8 MHz, CDCl3, 8-Werte)

Figure imgb0009

  • - olefinisches Proton : 5,71 ppm, s (verbreitert)
  • Δ1,4,17-BNC-Amid
1 H-NMR spectrum (8 MHz, CDCl 3 , 8 values)
Figure imgb0009
  • - olefinic proton: 5.71 ppm, s (broadened)
  • Δ 1,4,17 -BNC amide

ElementaranalyseElemental analysis

Figure imgb0010
Figure imgb0010

  • Δ4,17-BNC-AmidΔ 4.17 -BNC amide
ElementaranalyseElemental analysis

Figure imgb0011
Figure imgb0011

c) Herstellung der Isocyanatec) Preparation of the isocyanates

Die gemäß b) gewonnenen Säureamide werden in Tetrahydrofuran gelöst und unter Stickstoff mit einem geringen Überschuß an Bleitetraacetat zur Umsetzung gebracht. Zuvor ist das gesamte Reaktionssystem durch Stickstoffspülung gereinigt worden. Das Reaktionsgemisch wird für einen Zeitraum von 1,5 Stunden gerührt, danach ist die Reaktion abgeschlossen. Anschließend wird Natriumthiosulfat zur Reduktion eines eventuell noch vorliegenden Überschusses des Bleisalzes zugefügt. Die Reaktionslösung wird ein zweites Mal mit wäßrigem Thiosulfat und dann drei Mal mit gesättigter Kochsalzlösung gewaschen. Nach Phasentrennung und Trocknung der organischen Phase wird das Lösungsmittel abgezogen. Als Rückstand fallen die Isocyanatverbindungen an.The acid amides obtained in b) are dissolved in tetrahydrofuran and reacted under nitrogen with a slight excess of lead tetraacetate. The entire reaction system had previously been purged by nitrogen purging. The reaction mixture is stirred for a period of 1.5 hours, after which the reaction is complete. Sodium thiosulfate is then added to reduce any excess lead salt that may still be present. The reaction solution is washed a second time with aqueous thiosulfate and then three times with saturated saline. After phase separation and drying of the organic phase, the solvent is drawn off. The isocyanate compounds are obtained as a residue.

AnalysenwerteAnalytical values

  • Δ1,4-BNC-lsocyanatΔ 1,4 -BNC isocyanate
ElementaranalyseElemental analysis

Figure imgb0012
Figure imgb0012

1H-NMR-Spektrum (90 MHz, CDCI3, δ-Werte) :

Figure imgb0013

  • - olefinische Protonen : ABC-System mit Signalen bei : 6,02 ; 6,10 ; 6,12 ; 6,21 ; 6,23 ; 6,93 ; 7,05 ppm
  • IR-Spektrum (CH2 Cl2 [cm-1]) : 2 270, 1 662, 1 621, 1 602
  • Δ4-BNC-Isocyanat
1 H-NMR spectrum (90 MHz, CDCI 3 , δ values):
Figure imgb0013
  • - olefinic protons: ABC system with signals at: 6.02; 6.10; 6.12; 6.21; 6.23; 6.93; 7.05 ppm
  • IR spectrum (CH 2 Cl 2 [cm -1 ]): 2 270, 1 662, 1 621, 1 602
  • Δ 4 -BNC isocyanate

ElementaranalyseElemental analysis

Figure imgb0014
Figure imgb0014

d) Herstellung der Carbamated) Preparation of the carbamates

Die gemäß c) isolierten Isocyanatverbindungen werden in einem Überschuß eines niederen Alkohols, beispielsweise eines C-1 bis C-4 Alkoholes, und insbesondere in Methanol oder tert.-Butanol gelöst und zur Umsetzung gebracht. Der Überschuß des Alkohols wird abgezogen. Das entstandene Carbamat wird isoliert.The isocyanate compounds isolated according to c) are dissolved in an excess of a lower alcohol, for example a C-1 to C-4 alcohol, and in particular in methanol or tert-butanol and reacted. The excess alcohol is deducted. The carbamate formed is isolated.

AnalysenwerteAnalytical values

  • Δ1.4-BNC-PropylcarbamatΔ 1.4 -BNC propyl carbamate
  • Fp 159-161 °CMp 159-161 ° C
ElementaranalyseElemental analysis

Figure imgb0015
Figure imgb0015

1H-NMR-Spektrum (90 MHz, CDCl3, δ-Werte) :

Figure imgb0016

  • - olefinische Protonen : ABC-System mit Signalen bei : 6,04 ; 6,13 ; 6,15 ; 6,24 ; 6,27 ; 6,98 ; 7,10 ppm
  • IR-Spektrum (KBr, [cm-1]) : 3 350, 1 718, 1 668, 1 720 ; 1 700, 1 520
  • Δ1,4-BNC-Methylcarbamat
  • Fp 180-184 °C
1 H-NMR spectrum (90 MHz, CDCl 3 , δ values):
Figure imgb0016
  • - olefinic protons: ABC system with signals at: 6.04; 6.13; 6.15; 6.24; 6.27; 6.98; 7.10 ppm
  • IR spectrum (KBr, [cm -1 ]): 3,350, 1,718, 1,668, 1,720; 1,700, 1,520
  • Δ 1,4 -BNC methyl carbamate
  • Mp 180-184 ° C

ElementaranalvseElemental analysis

Figure imgb0017
Figure imgb0017

1H-NMR-Spektrum (80 MHz, CDCl3, δ-Werte) :

Figure imgb0018

  • ― olefinische Protonen : ABC-System mit Signalen bei : 6,06 ; 6,13 ; 6,16 ; 6,26 ; 6,28 ; 6,09 ; 7,11 ppm
  • Δ1,4,17-BNC-Methylcarbamat
1 H-NMR spectrum (80 MHz, CDCl 3 , δ values):
Figure imgb0018
  • - olefinic protons: ABC system with signals at: 6.06; 6.13; 6.16; 6.26; 6.28; 6.09; 7.11 ppm
  • Δ 1,4,17 -BNC-methyl carbamate

ElementaranalyseElemental analysis

Figure imgb0019
Figure imgb0019

  • Δ4-BNC-tert.-ButylcarbamatΔ 4 -BNC tert-butyl carbamate
  • Fp : 206-209 °CMp: 206-209 ° C
ElementaranalyseElemental analysis

Figure imgb0020
Figure imgb0020

1H-NMR-Spektrum (80 MHz, CDCl3, 8-Werte):

Figure imgb0021

  • - olefinisches Proton : 5,71 ppm, s (verbreitert).
1 H-NMR spectrum (80 MHz, CDCl 3 , 8 values):
Figure imgb0021
  • - olefinic proton: 5.71 ppm, s (broadened).

Claims (6)

1. Novel 20-substituted 3-oxo-pregn-4-ene steroid compounds and steroid compounds having optionally at least one further double bond in the 1(2)- and/or 17(20)-positions, represented by the general formula I
Figure imgb0024
in which X denotes the group ―CONH2, ―NCO or ―NHCOOR, wherein R is a lower hydrocarbon residue, 3-oxopregn-4-ene-20-carboxamide not being claimed here.
2. 3-oxo-pregna-1,4-diene-20-substituted steroid compounds represented by the general formula I, wherein X denotes the group -CONH2 or -NHCOOR.
3. 3-oxo-pregna-1,4,17(20)-triene-20-substituted steroid compounds represented by the general formula I, wherein X denotes the group -CONH2 or -NHCOOR.
4. A process for preparing 20-substituted 3-oxo-pregn-4-ene steroid compounds and steroid compounds having optionally at least one further double bond in the 1(2)- and/or 17(20)-positions, represented by the general formula I
Figure imgb0025
in which X has the following meaning : ―CONH2, ―NCO or ―NHCOOR, wherein R is a lower hydrocarbon residue, 3-oxopregn-4-ene-20-carboxamide not being claimed here, characterized in that, starting from 20-carboxylic acids corresponding to the general formula I (X = -COOH), first the 20-carboxylic acid halide (X = -CO-halogen) is prepared, and this compound is reacted with ammonia or ammonia-producing compounds to give the 20-carboxylic acid amide (X = ―CONH2, the latter, if desired, is rearranged into the 20-isocyanate (X = -NCO) by reaction with lead tetraacetate, and, if further desired, the 20-carbamate (X = -NHCOOR) is produced by the addition of an alcohol ROH (wherein R has the meaning as defined).
5. The process according to claim 4, characterized in that the 20-carbamate is produced in one step from the 20-acid amide without recovering the 20-isocyanate.
6. The process according to claims 4 and 5, characterized in that the reactions of the 20-acid amide to give the 20-isocyanate and/or the 20-carbamate are carried out in the absence of water and preferably in an inert atmosphere.
EP81101114A 1980-02-19 1981-02-17 New 20-substituted 3-oxo-pregn-4-ene steroid compounds and process for their preparation Expired EP0034364B1 (en)

Priority Applications (1)

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AT81101114T ATE10196T1 (en) 1980-02-19 1981-02-17 NEW 20-SUBSTITUTED 3-OXO-PREGNA-4-ENSTEROID COMPOUNDS AND PROCESSES FOR THEIR PRODUCTION.

Applications Claiming Priority (2)

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US06/122,397 US4255345A (en) 1980-02-19 1980-02-19 Steroid production
US122397 2002-04-16

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EP0034364A2 EP0034364A2 (en) 1981-08-26
EP0034364A3 EP0034364A3 (en) 1981-11-04
EP0034364B1 true EP0034364B1 (en) 1984-11-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046507A1 (en) 2006-10-13 2008-04-24 Sms Demag Ag Strand guiding device and method of operating it

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AT368759B (en) * 1980-05-12 1982-11-10 Henkel Kgaa METHOD FOR PRODUCING NEW STEROID-20CARBONS [URE COMPOUNDS
EP0039861B1 (en) * 1980-05-12 1984-08-15 Henkel Kommanditgesellschaft auf Aktien Process for the degradation of the 20-carboxy group of delta 1,4-bnc(bis-nor-cholanic acid) and of related steroid derivatives, as well as some nitrogen-containing steroids with 21 carbons
US4432905A (en) * 1980-05-12 1984-02-21 Henkel Kommanditgesellschaft Auf Aktien Simplified process for the degradation of steroid-C-22-carboxylic acids
DE3117529A1 (en) * 1980-05-12 1982-06-09 Henkel KGaA, 4000 Düsseldorf "METHOD FOR DEGRADING THE C-20 CARBOXYL GROUP IN (DELTA) 4 AND, IF NECESSARY, OTHER DOUBLE BONDING CONNECTIONS AND NEW C-21 STEROIDS"

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US4088760A (en) * 1976-06-23 1978-05-09 Richardson-Merrell Inc. Testosterone 5α-reductase inhibitors
US4191759A (en) * 1978-04-13 1980-03-04 Merck & Co., Inc. N-substituted-17β-carbamoylandrost-4-en-3-one 5α reductase inhibitors

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008046507A1 (en) 2006-10-13 2008-04-24 Sms Demag Ag Strand guiding device and method of operating it

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EP0034364A2 (en) 1981-08-26
US4255345A (en) 1981-03-10
JPS56128800A (en) 1981-10-08
EP0034364A3 (en) 1981-11-04
ATE10196T1 (en) 1984-11-15

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